3Doctoral School of Physiology and Pathophysiology, University Pierre and Marie Currie, Paris, 75005, France

4Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, CA,
91766, USA

5Department of Human Health and Development, University of Suceava, Suceava, 720229, Romania

Corresponding Author: Mihai Covasa Email: mcovasa{at}jouy.inra.fr

Abstract

Aberrations in gut microbiota are associated with metabolic disorders, including obesity. However, whether shifts in microbiota
profile during obesity is a characteristic of the phenotype or a consequence of obesogenic feeding remains elusive. Therefore,
we aimed to determine differences in the gut microbiota of obese-prone (OP) and obese-resistant (OR) rats and examined the
contribution of this microbiota to the behavioral and metabolic characteristics during obesity. We found that OP rats display
a distinct gut microbiota from obese-resistant OR rats fed the same high-fat diet, with a higher Firmicutes/Bacteroidetes
ratio and significant genera differences. Transfer of OP but not OR microbiota to GF mice replicated the characteristics of
the OP phenotype: reduced intestinal and hypothalamic satiation signaling, hyperphagia, increased weight gain and adiposity,
and enhanced lipogenesis and adipogenesis. Furthermore, increased gut permeability through conventionalization resulted in
inflammation via proinflammatory NF-κB/IKKβ signaling in adipose tissue, liver, and hypothalamus. OP donor and GF recipient
animals harbored specific species from Oscillibacter and Clostridium Clusters XIVa and IV, that were completely absent from OR animals. In conclusion, susceptibility to obesity is characterized by an unfavorable
microbiome predisposing the host to peripheral and central inflammation, promoting weight gain and adiposity during obesogenic
feeding.